In general, this invention relates to the treatment of various diseases using alkaline phosphatase and/or natriuretic peptide.
Numerous diseases and conditions involve abnormal skeletal function, structure, or growth of bone or cartilage. For some diseases, the etiology of these skeletal manifestations is known, such as in hypophosphatasia (HPP) and achondroplasia (ACH), but treatment options are limited. In other diseases, the etiology is unknown. For example, neurofibromatosis type I (NF1 or Von Recklinghausen disease) is an autosomal dominant genetic disorder having an incidence of approximately 1 in 3,500 live births. NF1 encodes neurofibromin, a member of the GTPase Activating Protein (GAP) family known to suppress the Ras kinase. Neurofibromin is a specific suppressor of p21-RAS, and mutations in the NF1 gene cause unsuppressed activation of RAS that lead to abnormal cell growth and differentiation. Accordingly, the clinical features of NF1 include various oncogenic transformations, such as neurocutaneous neurofibromas and optic pathway tumors, and other non-cancer manifestations, such as cognitive defects and skeletal abnormalities. Some of the NF1 skeletal manifestations have high morbidity (e.g., dystrophic scoliosis, long bone bowing, and pseudarthrosis) and unsatisfactory treatment options, which has been complicated by the fact that the etiology of these manifestations is unclear.
Many skeletal diseases arise from loss of function of one or more proteins. For example, hypophosphatasia (HPP) is a rare, heritable disease caused by one or more loss-of-function mutations in the gene ALPL, which encodes tissue-nonspecific alkaline phosphatase (TNALP; a.k.a. liver/bone/kidney type ALP). Alkaline phosphatase deficiency in osteoblasts and chondrocytes impairs skeletal mineralization, leading to symptoms of varying severity, from rickets or osteomalacia to almost complete absence of bone mineralization in utero. However, enzyme replacement therapy with unmodified alkaline phosphatase (e.g., infusion of native alkaline phosphatase) has been largely unsuccessful.
In another example, achondroplasia (ACH) is the most common form of short limb dwarfism in human beings, affecting more than 250,000 individuals worldwide, and is caused by mutations in the gene encoding fibroblast growth factor receptor 3 (FGFR3), which cause gain of FGFR3 function. The severity of the clinical phenotype is related to the capacity of the mutation to overactivate FGFR3 signaling pathways in chondrocytes, such as the MAP-kinase pathway. This pathway can be inhibited by activating the natriuretic peptide receptor B (NPR-B), which produces the second messenger cGMP, and cGMP, in turn, inhibits the MAP-kinase pathway inside the cell. In the cellular environment, the immature and mature forms of C-type natriuretic peptide (CNP), such as CNP53 and CNP22, bind to NPR-B and induce cGMP production in a dose-dependent and similar fashion. Thus, use of CNP or a CNP analog that could activate the NPR-B signaling pathway for the treatment of skeletal dysplasia has been considered. However, a major drawback of the therapeutic use of CNP is its extremely short half-life.
There is thus a need in the art to develop therapeutic molecules and methods for treating diseases having skeletal manifestations, such as neurofibromatosis. In addition, more therapeutic molecules are needed that have an appreciable half-life and/or other favorable pharmacokinetic and therapeutic properties, and these molecules can be used to treat a variety of disorders that would benefit from their underlying mode of action, such as neurofibromatosis, hypophosphatasia, and achondroplasia.